Metolachlor is a derivative of aniline and is a member of the chloroacetanilide herbicides used worldwide for control of broad-leaf weeds in corn, soybean, peanuts, sorghum, and cotton. Chemically metolachlor is known as 2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methyl) acetamide.

Metolachlor comprises four stereoisomers, two of which are inactive. The isomerism is based on a combination of a chiral center in the aliphatic side chain and a chiral axis between the phenyl group and the nitrogen atom. The originally formulated metolachlor was applied as a racemate, a 1:1 mixture of the (S)- and (R)-stereoisomers. It later came to be known that about 95% of the herbicidal activity of metolachlor exists in the two 1-S diastereomers. This meant that (S)-enantiomers provided high herbicidal activity than the (R)-enantiomers. Hence, work was initiated to provide a feasible enantioselective process resulting in enriching the isomeric ratio in favor of the (S) -enantiomers to increase the biological activity of the herbicide.

Initially, the search was for a suitable enantioselective catalyst which could produce (S)-metolachlor with high ee. Article titled “Enantioselective catalysis for agrochemicals. The case histories of (S)-metolachlor, (R)-metalaxyl and clozylacon” by Hans-Ulrich Blaser et. al in Topics in Catalysis, 4, (1997) 275-282, discusses the hydrogenation of both MEA and DMA imine with Rh diphosphine complexes. Under ambient conditions enantioselectivities in the range of 3-50% were obtained. Using [Rh(nbd)Cl]2/cycphos at −25° C., imine hydrogenation was achieved up to 69% enantiomeric excess which was far too low for an industrial application. Due to low reactivity of Rd complexes as enantioselective catalysts, the said article further discusses the synthesis of herbicide (S)-metolachlor (trade name DUAL MAGNUM) by enantioselective hydrogenation of an imine intermediate using iridium ferrocenyl-diphosphine catalyst with an enantioselectivity of 80%. An attempt to prepare all the three isomers of metolachlor-enamide with Rh or Ru/binap catalysts is also described with very little success.

Syngenta had identified the increased biological activity of the S-isomer pair of metolachlor and the technology to separate the isomers in 1982. However, separation as opposed to selective synthesis is inherently wasteful because it requires the disposal of the large volume of the less herbicidally active R-isomer pair that is not needed in S-metolachlor.
U.S. Pat. No. 5,886,225 (Jalett Hans-Peter et al.) relates to a process for the hydrogenation of imines of formula (I) with hydrogen under elevated pressure in the presence of iridium catalysts and with or without an inert solvent, wherein the reaction mixture contains hydrogen iodide to obtain amines of the formula (II). The optical yield ee is about 75-78%.

U.S. Pat. No. 6,822,118 (Hans-Pėter Jalett et al.) pertains to a process for the hydrogenation of imines with hydrogen under elevated pressure in the presence of iridium catalysts, Ir/ferrocenyl-diphosphine with or without an inert solvent, wherein the reaction mixture contains an ammonium or metal chloride, bromide or iodide and additionally an acid. The hydrogenation process yields amines with enantiomeric excess about 80%.
WO2009/136409 (Jaidev R. Shroff, et al.) relates to asymmetric hydrogenation of imine of Formula III under elevated pressure in presence of a catalyst system comprising a ligand complexed to a metal selected from iridium and rhodium or a salt thereof to obtain amine of Formula IV with greater than or equal to 76% ee, useful for the preparation of S-metolachlor. The invention further discloses that the process may optionally further comprises the addition of additive.

WO2006/003194 (Pugin, Benoit et al.) provides a process for the preparation of secondary amines by hydrogenation of ketimine in presence of iridium complex with chiral ferrocene tetraphosphines in which a secondary phosphine group and 1-secondary phosphinalk-1-yl are bound to each cyclopentadienyl ring in ortho positions. The configurational isomer obtained is preferably S-enantiomer where enantiomeric excess (ee) is at least 50%, preferably at least 60% and particularly at least 70%.
EP0605363 (Bader Rolf et al.) discloses a process for the preparation of 2-alkyl -6-methyl-N-(1′methoxy-2′-propyl)-aniline by catalytic reductive alkylation, wherein at least one mole equivalent of methoxyacetone is reacted with one mole equivalent of 2-alkyl-6-methyl-aniline in a liquid medium without an additional solvent, in the presence of a platinized carbon catalyst and hydrogen and in the presence of an acid co-catalyst under a hydrogen pressure of between 2×105 and 1×106 Pa at a temperature between 20° and 80° C., characterized in that the reaction mixture contains water from the beginning of the reaction and after the hydrogenation, base is added, the reaction mixture is filtered to separate the catalyst and the title compound recovered from the filtrate.
The processes described in the art based on asymmetric hydrogenation of imines, enamine or enamide for the synthesis of (S)-2-ethyl-N-(1-methoxypropan-2-yl)-6-methyl aniline, an important precursor in the synthesis of (S)-metolachlor, uses costly ligands as catalysts, harsh reaction conditions, additional use of other chemical additives and solvents making the process economically not viable. Further, the asymmetric hydrogenation of imines has several important drawbacks, such as the coordination of substrates, which can take place through both the nitrogen donor atom and the double bond, the E/Z isomeric mixture present in acyclic imines, and the poisoning effect of the resultant amines on the catalyst. Most importantly, the processes described in the art provide the end product with moderate optical purity, approx. ee 80%.
Keeping in view of the high biological activity of the ‘S’ enantiomer of Metolachlor as herbicides and the shortcomings of the prior art processes to obtain S-Metolachlor with high enantiopurity, the present inventors felt a need to provide an alternate route which is simple and effective for the preparation of (S)-2-ethyl-N-(1-methoxypropan-2-yl)-6-methyl aniline, a precursor of S-Metolachlor, with high enantiomeric excess (ee), by employing enantiopure (R)-epichlorohydrin as starting material, which will subsequently result in deriving S-Metolachlor with high ee.
Enantiopure epichlorohydrin (ECH) is a valuable epoxide intermediate for preparing optically active pharmaceuticals and other organic compounds. It undergoes various reactions with nucleophiles, electrophiles, acids, and bases because of the versatile reactivity of its epoxide ring. The present inventors have exploited the versatile reactivity of epichlorohydrin for synthesis of (S)-2-ethyl-N-(1-methoxypropan-2-yl)-6-methyl aniline with high selectivity.